Multiple System Atrophy (MSA) is a progressive neurodegenerative disease of undetermined cause that occurs sporadically and causes parkinsonism, cerebellar, pyramidal autonomic and urological dysfunction in any combination (Kaufman, H., Multiple System Atrophy, Neurology 1998, 11:351-55, citing The Consensus Committee of the American Autonomic Society and the American Academy of Neurology, Consensus statement on the definition of orthostatic hypotension, pure autonomic failure, and multiple system atrophy, Neurology 1996, 46:1470; Wenning et al., Multiple System Atrophy, Lancet Neurol. 2004, 3(2):93-103). The disease has historically been subcategorized by its predominant form of expression: striatonigral degeneration (SND) for parkinsonism, Shy-Drager syndrome (SDS) for autonomic failure, and sporadic olivopontocerebellar atrophy (OPCA) for cerebellar features.
However, glial cytoplasmic inclusions (GCI) in the brain of patients with MSA provide a pathological marker for the disorder (akin to Lewy bodies in Parkinson's disease), which confirms that SND, SDS and OPCA are the same disease with different clinical expression. (Kaufmann, supra, citing Lantos, P. L., Multiple System Atrophy, Brain Pathology 1997, 7:1293-97).
In addition, although MSA is often misdiagnosed as Parkinson's disease (PD), MSA is a separate and distinct disorder from PD. Both diseases cause stiffness and slowness in early stages, but the additional symptoms of MSA, such as dizziness and difficulty swallowing, are unusual in early PD. (Sarah Matheson Trust for MSA, at http://www.msaweb.co.uk/faq.htm).
Moreover, life expectancy in MSA is known to be shorter than in Parkinson's disease. An analysis of published case reports over a 100 year period showed that mean age of onset was 54 years (range 31-78) and survival 6 years (range 0.5-24). Survival was unaffected by gender, parkinsonian or pyramidal features, or whether the patient was classified as SND or OPCA (Ben-Schlomo et al. 1997).
As patients with MSA often present a predominantly parkinsonian form of the disorder (the striatonigral variety) or a largely cerebellar form (the OPCA-variety) new terms such as MSA-P and MSA-C have been proposed. (Gillman et al. 1999) Although most patients demonstrate one of these two forms, many have overlapping features, often with pyramidal tract deficit in addition to dysautonomic features (Mitra et al. 2003).
The most common symptoms of MSA-P include tremor, muscular rigidity and hypokinesia (decreased mobility, motor function or activity).
The most common symptoms of MSA-C include ataxia (failure of muscular coordination), impaired balance, impaired speech and impaired swallowing. (National Dysautonomia Research Foundation, at http://www.ndrf.org/MSA.htm). When the main presenting symptom is cerebellar, MSA may be confused with other cerebellar ataxias (Kaufmann 1998).
SDS or autonomic failure symptoms include: orthostatic hypotension, which includes lightheadedness, tiredness, blurred vision and pain in the rear of the neck; impotence, urinary incontinence or retention. Autonomic failure is present in 97% of cases (Rehman 2001). When the sole initial deficit is autonomic (i.e., orthostatic hypotension, erectile dysfunction), MSA mimics pure autonomic failure or an autonomic neuropathy.
There is no specific treatment for the various features of MSA and therefore medical treatment tends to be aimed at mitigating the parkinsonian and autonomic features of the disease (Colosimo et al 2002). Poor or no therapeutic response to levodopa is a well known characteristic of MSA-P. Dopamine agonists such as bromocriptine (Goetz et al 1984), lisuride (Lees et al 1981) and apomorphine (Rossi et al 2000) and glutamine antagonists such as amantadine have been tested with mixed results. Attempts to treat the autonomic dysfunction have focused on orthostatic hypotension therapies such as fludrocortisone and midodrine. Anticholinergics have been shown to help with the various urinary symptoms of the condition.
At present there is no recognized therapy for either treating MSA itself or its various features, leading at least one author to described the various therapeutic options currently available as ‘dismal’ (Kaufmann 1998).
Rasagiline, R(+)-N-propargyl-1-aminoindan, is a potent second generation monoamine oxidase (MAO) B inhibitor (Finberg et al., Pharmacological properties of the anti-Parkinson drug rasagiline; modification of endogenous brain amines, reserpine reversal, serotonergic and dopaminergic behaviours, Neuropharmacology (2002) 43(7):1110-8). Rasagiline Mesylate in a 1 mg tablet is commercially available for the treatment of idiopathic Parkinson's disease as AZILECT® from Teva Pharmaceuticals Industries, Ltd. (Petach Tikva, Israel) and H. Lundbeck A/S (Copenhagen, Denmark). Recent studies have demonstrated that, in addition to its MAO-B inhibitor activity, rasagiline possesses potent neuroprotective activity demonstrated by in vitro and in vivo experiments. Neuroprotection by rasagiline was achieved in animal models of closed head trauma (Huang et al., Neuroprotective effect of rasagiline, a selective monoamine oxidase-B inhibitor, against closed head injury in the mouse, Eur. J. Pharmacol. (1999) 366(2-3):127-35), global focal ischemia (Speiser et al., Studies with rasagiline, a MAO-B inhibitor, in experimental focal ischemia in the rat, J. Neural Transm. (1999) 106(7-8):695-606) and MPTP-induced neurotoxicity (Sage et al. 2001, 2003) as well as transgenic model of amyotrophic lateral sclerosis (Waibel et al., Rasagiline alone and in combination with riluzole prolongs survival in an ALS mouse model, J. Neurol. (2004) 251(9):1080-4) and 6-OHDA model of PD (Blandini et al., Neuroprotective effect of rasagiline in a rodent model of Parkinson's disease, Exp. Neurol. (2004) 187(2):455-9). Cell culture experiments have shown that rasagiline potently suppresses apoptotic cell death initiated by mitochondria (Youdim et al., Rasagiline [N-propargyl-1R-(+)-aminoindan], a selective and potent inhibitor of mitochondrial monoamine oxidase B Br. J. Pharmacol. (2001) 132(2):500-6; Akao et al., Mitochondrial permeability transition mediates apoptosis induced by N-methyl(R)salsolinol, an endogenous neurotoxin, and is inhibited by Bcl-2 and rasagiline, N-propargyl-1(R)-aminoindan, J. Neurochem. (2002) 82(4):913-23) by preventing preapoptotic swelling of mitochondria, caspase 3 activation, activation of nuclear PARP-1, translocation of GADPH, and nucleasomal DNA fragmentation (Youdim and Weinstock, Molecular basis of neuroprotective activities of rasagiline and the anti-Alzheimer drug TV3326 [(N-propargyl-(3R)aminoindan-5-YL)-ethyl methyl carbamate], Cell Mol. Neurobiol. (2001) 21(6):555-73; Youdim et al., Amyloid processing and signal transduction properties of antiparkinso-antialzheimer neuroprotective drugs rasagiline and TV3326, Ann. N.Y. Acad. Sci. (2003) 993:378-86; Bar-am et al., Regulation of protein kinase C by the anti-Parkinson drug, MAO-B inhibitor, rasagiline and its derivatives, in vivo, J. Neurochem. (2004) 89(5):1119-25; and Weinreb et al., Neuroprotectoin via pro-survival protein kinase C isoforms associated with Bcl-2 family members, Faseb J. (2004) 18(12):1471-3). Further, rasagiline induces increase of the anti-apoptotic Bcl-2 and Bcl-xL expression parallel to downregulation of pro-apoptotic Bad and Bax (Youdim et al., The essentiality of Bcl-2, PKC and proteasome-ubiquitin complex activations in the neuroprotective-antiapoptotic action of the anti-Parkinson drug, rasagiline, Biochem. Pharmacol. (2003) 66(8):1635-41; Yogev-Falach et al., The importance of propargylamine moiety in the anti-Parkinson drug rasagiline and its derivatives in MAPK-dependent amyloid precursor protein processing, Faseb J. (2003) 17(15):2325-7; Bar-Am et al., supra). Recent evidence from a delayed-start design study in PD has suggested potential disease-modifying efficacy of rasagiline also in a clinical setting (Parkinson Study, G., A controlled, randomized, delayed-start study of rasagiline in early Parkinson disease, Arch. Neurol. (2004) 61(4):561-6).